*Purpose: Patients with HCC meeting UNOS-downstaging (DS) criteria (1 lesion 5.1-8 cm, 2-3 lesions at least one 3.1-5 cm and total tumor diameter (TTD) ≤8 cm, or 4-5 tumors ≤3 cm with TTD ≤8 cm) have excellent LT outcomes after successful DS. However, the likelihood of successful DS and LT-related outcomes for “all-comers” (AC) patients with tumor burden initially exceeding UNOS-DS criteria is poorly understood.

*Methods: Consecutive patients with HCC meeting AC (n=82) or UNOS-DS criteria (n=230) at 7 LT centers in 4 UNOS regions were enrolled from 2015-2020 and prospectively followed to evaluate downstaging and LT outcomes.

*Results: Median pre-treatment characteristics between the AC and UNOS-DS groups did not significantly differ in terms of MELD (9 vs 9), Child-Pugh (CP) score (6 vs 6), and AFP (20 vs 12 ng/mL). TTD prior to first local-regional therapy (LRT) was 10.0 cm for AC (IQR 8.3-12.9) vs 6.2 cm for UNOS-DS (IQR 5.5-7.1) (p<0.001). AC patients required more LRT to be downstaged (2 vs 1; p=0.001) and had a lower probability of successful downstaging (69% vs 85% within 12 months; p<0.001). In multivariable (MV) analysis of the AC cohort, increasing sum of largest tumor diameter plus number of lesions prior to first LRT was negatively associated with successful downstaging (HR 0.82; p=0.026). Dropout probability due to tumor progression or death was similar at 3 years (AC 52% vs UNOS-DS 45%, p=0.27) with pre-treatment CP class B/C the only factor associated with dropout in the AC cohort (HR 2.58 vs CP A; p=0.009). Intention-to-treat (ITT) survival at 3 years was 69% for UNOS-DS vs. 58% for AC (p=0.07) and reduced to 23% in AC with CP B/C cirrhosis. Probability of LT at 3 years was 42% for AC vs. 58% in UNOS-DS (p=0.11) with no differences in explant tumor stage, grade, or vascular invasion. In the combined cohort, 39% were under-staged on explant. Factors associated with under-staging in MV logistic regression included increasing sum of largest tumor diameter plus number of lesions on last imaging prior to LT (OR 1.4; p=0.006) and AFP >20 (OR 6.4; p=0.004). Post-LT 2-year survival was 91% for AC vs 90% for UNOS-DS (p=0.67) with HCC recurrence observed in only 5% of AC after median post-LT follow-up of 19 mo.

*Conclusions: In this first prospective multi-regional comparative study on HCC downstaging, we observed an overall 70% probability of successful downstaging in AC with increasing pre-treatment tumor burden associated with unsuccessful downstaging. 3-year ITT survival in AC was nearly 60% though AC with CP B/C had poor survival. Explant pathology and 2-year post-LT outcome was similar between cohorts suggesting that LT is a reasonable goal in selected AC patients though efforts to improve under-staging are needed.

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